This is a competitive renewal for our RO1 (NS 051591), which is co-funded by the National Multiple Sclerosis Society (RG 3915), entitled A Combination Trial of Copaxone Plus Estriol in RRMS. This application is seeking funds to complete the ongoing trial its current form, with no funding requested for any newly proposed outcome measures or studies. Multiple sclerosis (MS) relapses are known to be significantly decreased during pregnancy, and estriol is a major estrogen of pregnancy. Using the preclinical model of MS, experimental autoimmune encephalomyelitis (EAE), estrogen treatments, including estriol, when administered at pregnancy doses were shown to be both anti-inflammatory through a variety of immune mechanisms, as well as directly neuroprotective. Next, in a pilot clinical trial, it was demonstrated that treatment of 6 RRMS subjects with oral estriol for six months resulted in a significant (80%) reduction in gadolinium enhancing lesions on serial brain MRIs, caused a favorable shift in cytokine production by immune cells and decreased levels of the immune cell migration marker matrix metalloprotease-9 (MMP-9). Treatment duration of six months was too short to assess treatment effects on relapses. This proposal will establish whether treatment with oral estriol, the major estrogen of pregnancy, induces a decrease in relapses in RRMS subjects when used in combination with injectable Copaxone. This study intends to establish proof-of-principle, safety and set the parameters for a future phase III study and to establish the criteria for appropriate power calculation. Combination treatment with Copaxone injection plus estriol pill (8 mg per day) will be compared to Copaxone injection plus placebo pill in a multicenter, double blinded trial, with 65 subjects in each arm. The duration of treatment will be two years and the primary outcome measure will be relapse rate. Secondary outcomes will include disability measures (MSFC, EDSS, 7-24 MS Quality of Life, Modified Fatigue Impact Scale and Beck Depression Inventory) and MRI markers (enhancing lesions, new T2 lesions, atrophy). Safety measures (blood tests and gynecologic evaluations) will also be followed. The overall goal of this study will be the development of a safe, oral treatment, estriol, for RRMS.